Clinical studies We are exploring the role of damage to specific brain areas, including the reward pathways, in the genesis of fatigue, amotivation, and other common, unexplained complaints of military personnel returning from deployment. This study combines intensive neuroimaging with standard and experimental behavioral measures focusing on effort generation. Another study in collaboration with the Naval Medical Research Center and the Walter Reed Army Institute of Research is looking for evidence of behavioral and brain changes in military personnel with occupational exposure to blast. Neurophysiological probe studies Methylphenidate and other psychomotor stimulants have been helpful for cognitive deficits, notably mental slowness, in traumatic brain injury (TBI). These agents also increase intrinsic inhibition in the motor cortex in healthy subjects and patients with attention deficit-hyperactivity disorder, presumably via a catecholaminergic mechanism. However, the response is highly variable across patients. This could be related to the degree of damage to the dopamine system. In a collaboration with Drs. Ramn Diaz-Arrast&#299;a and Nora Volkow, we are examining changes in motor cortex inhibition produced by methylphenidate in TBI patients and looking for correlations with clinical response and changes in dopamine binding, measured by raclopride PET scanning. Measurment of intracortical inhibition could be a safe and easy screen for stimulant response if it predicts clinical and/or PET outcomes in TBI. We have used theta-burst transcranial magnetic stimulation (TMS) of the motor and premotor cortex to produce a temporary impairment on learning tasks and shown that adding rewarded feedback to the same task can overcome this temporary deficit. This may have significant implications for enhancing procedural learning in clinical rehabilitation and skill training. Interestingly, the effect of inhibitory stimulation of the motor cortex on motor evoked potentials did not correlate with the effect on learning, suggesting that the effect on learning is not mediated by an anti-plastic change in the motor output system. When we examined the effect of theta-burst TMS of the motor cortex with functional MRI, we found that it did not shut down the motor cortex or produce ay other focal change in brain activity. Rather, it caused a shift in task-related connectivity between brain areas, away from a previously described learning network made up of motor areas and toward another learning network including areas related to vision and spatial relations. This finding shows that the effects of focal TMS are subtle and distributed, rather than being a virtual lesion analogous to focal brain damage, as has been posited. Moreover, it suggests the possibility of influencing or rerouting learning processes, a possible strategy for learning enhancement in clinical populations. We are currently examining the effects of inhibitory TMS of the motor and prefrontal cortex on procedural learning of a non-motor task, with and without feedback.